The present invention relates to N-acyl derivatives of an amino sugar with an oligopeptide, endowed with antitumor chemotherapeutic activity, and to pharmaceutical compositions containing said derivatives.
Antitumor chemotherapy has been and still is an object of intensive research. Certain positive results have undoubtedly been achieved, especially by means of polychemotherapy realized by associating different active substances according to carefully developed protocols. However, the ideal therapy has not yet been found. The need to find new active substances has been particularly emphasized. All the foregoing justifies continuous research directed towards preparing new chemotherapeutic compounds active against tumors. There are already known peptides having antitumor activity, consisting of both normal and antimetabolic amino acids, coupled by means of a peptide bond. Such peptides have for years been in therapeutic use with favorable results both in monochemotherapy and in polychemotherapy. However, there adoption encounters obstacles of various kinds, which are connected, among other things, with the impossibility of being administered by the oral route because of inactivation of the said peptides in the gastrointestinal tract.
In my copending U.S. application Ser. No. 929,237 there is disclosed a series of compounds possessing antitumor activity against transplanted tumors in animals characterized by the presence of a molecule of a glucosamine. The antitumor chemotherapeutic activity of those compounds is also reported in an article by the inventor entitled "N-Acyl Derivatives of Glucosamine with Oligo-Peptides," Current Chemotherapy, American Society of Microbiology, p. 1183 (April 1978). The glucosamine is used as a carrier of an antitumor-active compound wherein the antitumor-active molecule is bound to the --NH.sub.2 of the glucosamine. For example, the amino group of the glucosamine is acylated by the carboxyl group of an antitumor amino acid or peptide. The compounds disclosed in said copending application and in said article are of the general formula: ##STR2## where R.sub.1 is a hydrogen atom or an acetyl group,
R.sub.2 is a hydrogen atom, an acetyl group, aliphatic (C.sub.1 -C.sub.6) group or a benzyl group, and PA1 R.sub.3 is m-di(2-chloroethyl)amino-L-phenylalanine, or L-methionyl-m-di(2-chloroethyl)amino-L-phenylalanyl-p-fluoro-L-phenylalani ne, or p-fluoro-L-phenylalanyl-m-di(2-chloroethyl)amino-L-phenylalanyl-L-proline, or m-di(2-chloroethyl)amino-L-phenylalanyl-L-methionyl-p-fluoro-L-phenylalani ne.
By investigating the chemotherapeutic effect afforded by substituting other peptides besides those listed above at the R.sub.3 position in the above-mentioned formula, novel compounds were obtained wherein an oligopetide is covalently bonded to two molecules of a D-hexosamine or other amino sugars such as glucosamine, galactosamine, or mannosamine through peptide linkages between the amino groups of the amino sugar molecules and the two carboxylic acid groups of the aspartic acid portion of the oligopeptide.
The resulting N-acyl derivatives of the amino sugars of the present invention are not inactivated in the gastrointestinal tract and are useful in controlling transplanted neoplasms in animals.